In collaboration with 10 academic centers across the United States, we have recruited a large sample of families in which at least 2 siblings suffer from bipolar disorder or related mood disorders. This is the largest sample ever to participate in a genetic study of bipolar disorder. All research participants have undergone a diagnostic interview and provided a blood sample for DNA analysis. Genetic linkage studies have been performed using molecular markers evenly spaced across all chromosomes. These studies suggest that regions on chromosomes 6, 8, 13, 17, 18, and 22, among others, may contain genes that contribute to bipolar disorder in these families. Ongoing work is aimed at identifying the actual genes involved. Using the latest genotyping chip technology and DNA pooling, we performed and conducted the first genome-wide association study of bipolar disorder. The results implicated several genes, each of small effect, suggesting that bipolar disorder is a polygenic disease. Meta-analysis of independent case-control studies of bipolar disorder supported association with 3 distinct genes that play a role in zinc metabolism, cell adhesion, and maintenance of normal neuronal functioning. In collaboration with other investigators at the NIMH Intramural Program, we have also investigated neuroimaging measures that have been associated with bipolar disorder and may reveal biological aspects of the disease. We have carried out candidate gene and genome-wide association studies of serotonin-transporter binding potential, as measured by positron emission tomography, and amygdala activation, measured by functional magnetic resonance imaging. These studies have implicated additional genes that were not detected in our studies that were based solely on the clinical diagnosis. Ongoing work is aimed at correlating our results with those of other genome-wide association studies, studying the genes that seem to play the biggest role in disease risk, and dissecting which aspects of bipolar disorder are best explained by each risk gene.